We propose to test the hypothesis that a human locus, analogous to the murine T locus and located in or near the major histocompatibility complex (HLA), contributes to neural tube defects (NTD) and recurrent involuntary fetal wastage. This model proposes that some affected fetuses are homozygous for recessive mutant "t" alleles. Given the linkage disequilibrium of alleles at HLA loci in humans and of alleles of the murine H-2/T locus model, and the likely heterogeneity in NTD, our approach to testing this model is two-fold. First we will examine the frequency and extent of HLA-A,B compatibility of couples who have borne an NTD child or who have experienced recurrent involuntary fetal wastage, in comparison with control couples with 3 or more pregnancies and no fetal wastage or major developmental abnormalities. Preliminary data is supportive of our hypothesis in that parents of NTD offspring or couples experiencing recurrent abortions do show greater HLA-A,B compatibility than controls. Second, using a 51chromium release assay, sera from women who have borne an NTD affected fetus, experienced fetal wastage or have unremarkable obstetrical histories will be tested for non-HLA antibody to target cells likely to express the product of the putative human T locus: teratoma cell lines, including Tera-2 derived from an undifferentiated teratoma, and male germ line cells. With these approaches, we will evaluate evidence of a genetic contribution to NTD and involuntary fetal loss in the HLA region and develop immunological probes for the products of the putative loci: tools for studies of the biology and genetics of normal and abnormal human fetal development.